Tumour interstitial fluid-enriched phosphoethanolamine suppresses T cell function

Nutrient stress represents an important barrier for anti-tumour immunity, and tumour interstitial fluid often contains metabolites that hinder immune function. However, it is difficult to isolate the effects of tumour nutrient stress from other suppressive factors. Thus, we used a chemically defined cell culture medium based on the metabolomic profile of tumour interstitial fluid: tumour interstitial fluid medium (TIFM). Culture of CD8⁺ T cells in TIFM limited cell expansion and impaired CD8⁺ T cell effector functions upon restimulation, suggesting that tumour nutrient stress alone is sufficient to drive T cell dysfunction. We identified phosphoethanolamine (pEtn), a phospholipid intermediate, as a driver of T cell dysfunction. pEtn dampened T cell receptor signalling by depleting T cells of diacylglycerol required for T cell receptor signal transduction. The reduction of pEtn accumulation in tumours improved intratumoural T cell function and tumour control, suggesting that pEtn accumulation plays a dominant role in immunosuppression in the tumour microenvironment.